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Pharmacogenomics of Antihypertensive Treatment & Clinical Pharmacological Studies of Digoxin Treatment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In Part I we found that the CYP2C9 genotype appears to influence the diastolic blood pressure response to the angiotensin II-receptor antagonist irbesartan in patients with hypertension and left ventricular hypertrophy. Those with the *1/*2 genotype (slower metabolism) responded better than those with the *1/*1 genotype (normal metabolism), likely due to a slower elimination of the drug. We further found that a +9/-9 exon 1 polymorphism of the B2 bradykinin receptor gene – shown to affect mRNA expression - appears to influence the regression of left ventricular mass during therapy with irbesartan or the beta-blocker atenolol in the same patients. Subjects with the -9/-9 genotype (higher mRNA expression) had a greater regression than carriers of the +9 allele.

In Part II we found that women on digoxin therapeutic drug monitoring have higher serum digoxin concentrations (SDCs) as compared to men (1.54±0.04 [nmol/L±SE] vs 1.20±0.05 [nmol/L±SE], p<0.001), which could be of importance since an SDC >1.4 nmol/L has been associated with increased mortality. We further found that coadministration of P-glycoprotein inhibitors with digoxin was common (47%) among the same patients, and that the SDC increased in a stepwise fashion with the number of P-glycoprotein inhibitors (20-60%). Lastly, we found that patients admitted to Swedish coronary care units with atrial fibrillation without heart failure and who had been given digoxin had a higher 1-year mortality than those not given digoxin (RR 1.44 [95% CI 1.29-1.60], adjustment made for potential confounders).

In conclusion, Part I represents a further step in the pharmacogenomic prospect of tailoring antihypertensive therapy. Part II indicates that heightened attention to the digoxin-dose is warranted in women, that there is a need for awareness about P-glycoprotein interactions with digoxin, and that long-term therapy with digoxin is an independent risk factor for death among patients with atrial fibrillation without heart failure.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2005. , p. 107
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 36
Keyword [en]
Molecular medicine, pharmacogenomics, irbesartan, atenolol, hypertension, digoxin, RIKS-HIA, atrial fibrillation, heart failure
Keyword [sv]
Molekylärmedicin
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-5782ISBN: 91-554-6241-3 (print)OAI: oai:DiVA.org:uu-5782DiVA, id: diva2:166369
Public defence
2005-05-25, Enghoffsalen, Entrance 50, Uppsala University Hospital, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2005-05-04 Created: 2005-05-04 Last updated: 2018-01-13Bibliographically approved
List of papers
1.
The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
2. B2 bradykinin receptor (B2BKR) polymorphism and change in left ventricular mass in response to antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial
Open this publication in new window or tab >>B2 bradykinin receptor (B2BKR) polymorphism and change in left ventricular mass in response to antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial
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2003 (English)In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 21, no 3, p. 621-4Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system, including left ventricular (LV) hypertrophy. Studies have demonstrated that bradykinin, through the B2 bradykinin receptor (B2BKR), mediates important cardiovascular effects that may protect against LV hypertrophy. Recently, a +9/-9 exon 1 polymorphism of the B2BKR was shown to be strongly associated with LV growth response among normotensive males undergoing physical training. We aimed to clarify whether the processes found in exercise-induced LV growth in normotensive people also occur in pathological LV hypertrophy. DESIGN AND METHODS: We determined the B2BKR genotype of 90 patients with essential hypertension and echocardiographically diagnosed LV hypertrophy, included in a double-blind study to receive treatment for 48 weeks with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol. RESULTS: B2BKR +9/+9 genotypes responded poorly in LV mass regression, independent of blood pressure reduction or treatment, as compared to the other genotypes (adjusted mean change in LV mass index = -10.0 +/- 4.6 versus -21.6 +/- 2.2 g/m2, P = 0.03). CONCLUSIONS: Our results suggest an impact of the B2BKR polymorphism on LV mass regression during antihypertensive treatment.

Keyword
Adrenergic beta-Antagonists/therapeutic use, Angiotensin II Type 1 Receptor Blockers, Antihypertensive Agents/*therapeutic use, Atenolol/*therapeutic use, Biphenyl Compounds/*therapeutic use, Double-Blind Method, Female, Genotype, Humans, Hypertension/*drug therapy/*genetics/pathology, Hypertrophy; Left Ventricular/*drug therapy/*genetics/pathology, Male, Middle Aged, Organ Size/drug effects, Polymorphism; Genetic, Receptor; Bradykinin B2/*genetics, Research Support; Non-U.S. Gov't, Sweden, Tetrazoles/*therapeutic use
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-73227 (URN)10.1097/01.hjh.0000052474.40108.c9 (DOI)12640257 (PubMedID)
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-14Bibliographically approved
3.
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4.
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5. The effect of digoxin on mortality – a cohort study of patients with atrial fibrillation, heart failure or both
Open this publication in new window or tab >>The effect of digoxin on mortality – a cohort study of patients with atrial fibrillation, heart failure or both
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-93020 (URN)
Available from: 2005-05-04 Created: 2005-05-04 Last updated: 2010-01-13Bibliographically approved

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